Theta class glutathione S-transferase GSTT1 genotypes and susceptibility to cervical neoplasia: interactions with GSTM1, CYP2D6 and smoking

Abstract

The factors that determine progression of cervical intra-epithelial neoplasia (CIN) to squamous cell carcinoma (SCC) are unknown. Cigarette smoking is a risk factor, suggesting polymorphism at loci that encode carcinogen-metabolizing enzymes such as glutathione S-transferase (GSTT1, GSTM1) and cytochrome P450 (CYP2D6) may determine susceptibility to these cancers. We have studied the frequency of the null genotype at the theta class GSTT1 locus in women with low-grade CIN, high-grade CIN and SCC. The control group comprised women with normal cervical pathology suffering menorrhagia. We found the frequency of GSTT1 null in the control and case groups was not significantly different, though frequency distributions of combinations of the genotype with smoking in mutually exclusive groups in the high-grade CIN group and the other case groups were significantly different. Interactive effects of GSTT1 null with the GSTM1 null and CYP2D6 EM genotypes, and cigarette smoking were also studied by comparing the multinomial frequency distributions of these factors over mutually exclusive categories. These showed no significant differences between the controls and SCC or low-grade CIN. Frequency distributions in high-grade CIN, however, were significantly different to the controls, and both SCC and low-grade CIN; frequency distributions of GSTT1 null with smoking and CYP2D6 EM, individually and in combination, were significantly different. However, inspection of our data does not indicate that GSTT1 null is a major factor mediating risk. Thus, comparison of chi 2 values for the differences between frequency distributions in high-grade CIN and other groups shows that values for combinations of GSTT1 null with other factors are lower than those for equivalent combinations with smoking and CYP2D6 EM. Interestingly, the combination GSTT1 null/GSTM1 null did not appear to influence susceptibility to CIN or SCC.

Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender

“…Recent studies showing the interactive effects of GSTM1 and CYPlAl genotypes suggest that the influence of detoxifying enzymes in mediating cancer risk will depend on allelism at other relevant loci (Nakachi et al, 1993;Warwick et al, 1994). We identified no significant interactions between the putatively poor detoxification genotypes, GSTM1 null, GSTT1 null and CYP2D6 EM but did find significant differences between controls and patients with multiple BCC in the frequency of the combinations GSTM 1 A/B with CYP2D6 EM and, GSTM1 A/B with GSTT1 expressers.…”

“…It does not distinguish the GSTMI*O/GSTMI*A and GSTMI*A/GSTMI*A genotypes or the equivalent Susceptibility to multiple BCC A Heagerty et al 45 GSTM1 B genotypes (Fryer et al, 1993). GSTT1 null and expressing subjects were identified by PCR using the primer set and reaction conditions described by Pemble et al (1994) and Warwick et al (1994). The two mutant CYP2D6 alleles (G-*A transition at intron 3/exon 4 and base pair deletion in exon 5) were identified (Gough et al, 1990;Wolf et al, 1992).…”

Co-fatores do HPV na oncogênese cervical

“…Os dois mecanismos principais pelo qual o hábito de fumar contribui para a oncogênese cervical incluem a exposição direta do DNA de células epiteliais cervicais a nicotina e a cotidina, e a produtos metabólicos do tipo esperado a partir de reações com hidrocarbonetos policíclicos aromáticos e aminas aromáticas, outros componentes da fumaça do cigarro 23,46 . As associações entre diferentes genótipos de enzimas carcinógenas-metabolizantes, fumo e neoplasia cervical foram investigadas por dois estudos de Warwick et al 1,56,57 . O primeiro estudo deste autor concluiu que fumantes com o genótipo tipo selvagem da enzima detoxificante citocromo P450 fase 1 (CYP2D6), genótipo metabolizador extensivo (EM), têm um risco aumentado para NIC II/III, mas um risco reduzido para carcinoma escamoso cervical invasivo 13 .…”

“…De qualquer modo, os carcinógenos necessários para a progressão para neoplasia invasora e presumidamente efetivamente degradados por CYP2D6-EM ainda não são conhecidos. O segundo estudo realizado por Warwick et al não encontrou associação significativa entre outro genótipo da S-transferase classe theta glutationa (GSTT1) e a neoplasia cervical, da mesma forma do que foi verificado anteriormente com o genótipo S-transferase glutationa fase 2 (GSTM1), por este mesmo autor 56,57 .…”

Glutathione S-transferase M1 and T1 polymorphisms and cervical cancer risk: A meta-analysis

“…According to the exclusion criteria, 15 articles were excluded including 5 articles containing overlapping population [7][8][9][10][11], 8 precancerous lesions included in the cases [12][13][14][15][16][17][18][19], 2 without sufficient data [20][21]. At last, data were available from 16 individual case-control studies [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], Table 1 presented characteristics of these 16 case-control studies (a total of 1,627 CC cases and 2,161 controls). 14 studies on GSTM1 polymorphism (a total of 1,514 CC cases and 1,907 controls), 12 studies on GSTT1 polymorphism (a total of 1,187 CC cases and 1,590 controls), and 6 studies on GSTM1-GSTT1 interaction analysis (a total of 791 CC cases and 767controls) were included in the meta-analysis.…”